Skip to main content

Advertisement

SpringerLink
Log in

P21 and p27 Immunoexpression in Upper Urinary Tract Urothelial Carcinomas

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

p21 and p27 are members of cyclin-dependent kinase family, which function as tumor suppressors and they are involved in development and progression of several malignancies. We investigated their expression in upper urinary tract urothelial carcinoma (UUTUC). Radical nephroureterectomy materials of 34 patients were assessed by immunohistochemistry to evaluate expression of p21 and p27 in UUTUC. Results were correlated with various clinicopathological variables as age, gender, tumor grade and stage, tumor architecture, multifocality, subsequent bladder carcinoma development and clinical outcome.

p21 and p27 expression was observed in 52.9 % (n = 18) and 88.2 % (n = 30), respectively. A total of 21 tumors (61.7 %) showed either total loss of p21 expression (n = 16, 47 %) or lower expression (n = 5, 14.7 %). No correlation was found between p21 expression and clinicopathologic variables. Cases showing total loss or lower p27 expression (11.7 % and <25.6 %, respectively) (n = 19, 55.8 %) constituted 67.6 % (n = 23) of the cases totally. This loss or lower p27 expression correlated with a shorter overall survival in both univariate and multivariate analysis (p = 0.039 and p = 0.037, respectively). None of the noninvasive tumors (papillary and nodular tumors) showed loss of p27 (p = 0.016) while 33.3 % of invasive ones showed p27 loss. Noninvasive tumor architecture also correlated with subsequent bladder carcinoma development (p = 0.032) while invasive tumor architecture correlated with advanced stage (T3 and T4) (p = 0.003). p27 is widely expressed in UUTUC, while p21 expression is observed in half of the cases. Loss of p27 expression correlated with tumor architecture and overall survival in UUTUC. However, further research is needed to assess their role in UUTUC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249

    Article  PubMed  Google Scholar 

  2. Novara G, De Marco V, Gottardo F, Dalpiaz O, Bouygues V, Galfano A, et al. (2007) Independent predictors of cancer-specific survival in transitional cell carcinoma of the upper urinary tract: multiinstitutional dataset from 3 European centers. Cancer 110(8):1715–1722

    Article  PubMed  Google Scholar 

  3. Chromecki TF, Cha EK, Fajkovic H, Margulis V, Novara G, Scherr DS, et al. (2012) The impact of tumor multifocality on outcomes in patients treated with radical nephroureterectomy. Eur Urol 61(2):245–253

    Article  PubMed  Google Scholar 

  4. Verhoest G, Shariat SF, Chromecki TM, Raman JD, Margulis V, Novara G, et al. (2011) Predictive factors of recurrence and survival of upper tract urothelial carcinomas. World J Urol 29(4):495–501

    Article  PubMed  PubMed Central  Google Scholar 

  5. Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, et al. (1997) Decreased levels of the cell-cycle inhibitor p27Kip1 protein; prognostic implications in primary breast cancer. Nat Med 3(2):227–230

    Article  CAS  PubMed  Google Scholar 

  6. Cote RJ, Susan Y, Groshen S, Alexander GM, Gatti LA, Firpo EJ, et al. (1998) Association of p27Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. J Natl Cancer Inst 90(12):916–920

    Article  CAS  PubMed  Google Scholar 

  7. Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, et al. (1997) Increased proteasomedependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3(2):231–234

    Article  CAS  PubMed  Google Scholar 

  8. Shariat SF, Zlotta AR, Ashfaq R, Sagalowsky AI, Lotan Y (2007) Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness. Mod Pathol 20(4):445–459

    Article  CAS  PubMed  Google Scholar 

  9. Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC, et al. (1999) p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154(2):313–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Korkolopoulou P, Konstantinidou AE, Thomas-Tsagli E, Christodoulou P, Kapralos P, Davaris P (2000) WAF1/p21 protein expression is an independent prognostic indicator in superficial and invasive bladder cancer. Appl Immunohistochem Mol Morphol 8(4):285–292

    CAS  PubMed  Google Scholar 

  11. Shariat SF, Karakiewicz PI, Ashfaq R, Lerner SP, Palapattu GS, Cote RJ, et al. (2008) Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy. Cancer 112(2):315–325

    Article  PubMed  Google Scholar 

  12. Matsushima H, Sasaki T, Goto T, Hosaka Y, Homma Y, Kitamura T, et al. (1998) Immunohistochemical study of p21WAF1 and p53 proteins in prostatic cancer and their prognostic significance. Hum Pathol 29(8):778–783

    Article  CAS  PubMed  Google Scholar 

  13. Masuda M, Takano Y, Iki M, Makiyama K, Ikeda I, Noguchi S, et al. (2000) Cyclin-dependent kinase inhibitor p27kip1 expression in transitional cell carcinoma of renal pelvis and ureter. Cancer Lett 150(2):183–189

    Article  CAS  PubMed  Google Scholar 

  14. Kamai T, Takagi K, Asami H, Ito Y, Arai K, Yoshida KI (2000) Prognostic significance of p27kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter. BJU Int 86(1):14–19

    Article  CAS  PubMed  Google Scholar 

  15. Fromont G, Rouprêt M, Amira N, Sibony M, Vallancien G, Validire P, et al. (2005) Tissue microarray analysis of the prognostic value of E-cadherin, Ki67, p53, p27, survivin and MSH2 expression in upper urinary tract transitional cell carcinoma. Eur Urol 48(5):764–770

    Article  CAS  PubMed  Google Scholar 

  16. Gakis G, Schwentner C, Todenhöfer T, Stenzl A (2012) Current status of molecular markers for prognostication and outcome in invasive bladder cancer. BJU Int 110(2):233–237

    Article  CAS  PubMed  Google Scholar 

  17. Simsir A, Sarsik B, Cureklibatir I, Sen S, Gunaydin G, Cal C (2011) Prognostic factors for upper urinary tract urothelial carcinomas: stage, grade, and smoking status. Int Urol Nephrol 43(4):1039–1045

    Article  CAS  PubMed  Google Scholar 

  18. Sobin LH, Gospodarowicz MK, Wittekind C, eds. TNM classification of malignant tumors, ed. 7. UICC International Union Against Cancer. Hoboken, NJ: Wiley-Blackwell; 2010. p. 258–265.

  19. Eble JN, Sauter G, Epstein JI, et al. World Health Organization classification of tumours. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon, France: IARC Press; 2004, p.90.

  20. Remzi M, Haitel A, Margulis V, Karakiewicz P, Montorsi F, Kikuchi E, et al. (2009) Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int 103(3):307–311

    Article  PubMed  Google Scholar 

  21. Doganavsargil B, Simsir A, Boyacioglu H, Cal C, Hekimgil M (2006) A comparison of p21 and p27 immunoexpression in benign glands, prostatic intraepithelial neoplasia and prostate adenocarcinoma. BJU Int 97:644–648

    Article  CAS  PubMed  Google Scholar 

  22. Romics I, Bánfi G, Székely E, Krenács T, Szende B (2008) Expression of p21(waf1/cip1), p27 (kip1), p63 and androgen receptor in low and high Gleason score prostate cancer. Pathol Oncol Res 14(3):307–311

    Article  PubMed  Google Scholar 

  23. Huang LW, Seow KM, Lee CC, Lin YH, Pan HS, Chen HJ (2010) Decreased p21 expression in HPV-18 positive cervical carcinomas. Pathol Oncol Res 16(1):81–86

    Article  CAS  PubMed  Google Scholar 

  24. Fritsche HM, Novara G, Burger M, Gupta A, Matsumoto K, Kassouf W, et al. (2012) Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma. Urol Oncol 30(5):666–672

    Article  PubMed  Google Scholar 

  25. Margulis V, Youssef RF, Karakiewicz PI, Lotan Y, Wood CG, Zigeuner R, et al. (2010) Preoperative multivariable prognostic model for prediction of nonorgan confined urothelial carcinoma of the upper urinary tract. J Urol 184(2):453–458

    Article  PubMed  Google Scholar 

  26. Franke KH, Miklosi M, Goebell P, Clasen S, Steinhoff C, Anastasiadis AG, et al. (2000) Cyclin-dependent kinase inhibitor P27 (KIP1) is expressed preferentially in early stages of urothelial carcinoma. Urology 56(4):689–695

    Article  CAS  PubMed  Google Scholar 

  27. Hisataki T, Miyao N, Masumori N, Takahashi A, Sasai M, Yanase M, et al. (2000) Risk factors for the development of bladder cancer after upper tract urothelial cancer. Urology 55(5):663–667

    Article  CAS  PubMed  Google Scholar 

  28. Koga F, Nagamatsu H, Ishimaru H, Mizuo T, Yoshida K (2001) Risk factors for the development of bladder transitional cell carcinoma following surgery for transitional cell carcinoma of the upper urinary tract. Urol Int 67(2):135–141

    Article  CAS  PubMed  Google Scholar 

  29. Raman JD, Ng CK, Scherr DS, Margulis V, Lotan Y, Bensalah K, et al. (2010) Impact of tumor location on prognosis for patients with upper tract urothelial carcinoma managed by radical nephroureterectomy. Eur Urol 57(6):1072–1079

    Article  PubMed  Google Scholar 

  30. Clasen S, Schulz WA, Gerharz CD, Grimm MO, Christoph F, Schmitz-Dräger BJ (1998) Frequent and heterogeneous expression of cyclin-dependent kinase inhibitor WAF1/p21 protein and mRNA in urothelial carcinoma. Br J Cancer 77(4):515–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zlotta AR, Noel JC, Fayt I, Drowart A, Van Vooren JP, Huygen K, et al. (1999) Correlation and prognostic significance of p53, p21 WAF1/CIP1 and Ki67 expression in patients with superficial bladder tumors treated with bacillus Calmette-Guerin intravesical therapy. J Urol 161(3):792–798

    Article  CAS  PubMed  Google Scholar 

  32. Stein JP, Ginsberg DA, Grossfeld GD, Chatterjee SJ, Esrig D, Dickinson MG, et al. (1998) Effect of p21 WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst 90(14):1072–1079

    Article  CAS  PubMed  Google Scholar 

  33. Philipp-Staheli J, Kim KH, Liggitt D, Gurley KE, Longton G, Kemp CJ (2004) Distinct roles for p53, 27Kip1, and p21Cip1 during tumor development. Oncogene 23(4):905–913

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Ege University Faculty of Medicine, Bornova, 35100, Izmir, Turkey

    Banu Sarsik, Basak Doganavsargil & Sait Sen

  2. Department of Urology, Ege University Faculty of Medicine, Izmir, Turkey

    Adnan Simsir & Cag Cal

  3. Department of Pathology, Mugla University Education and Research Hospital, Mugla,, Turkey

    Ayse Yazici

  4. Department of Pathology, Adiyaman University Training and Research Hospital, Adiyaman, Turkey

    Burcin Pehlivanoglu

Authors
  1. Banu Sarsik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Basak Doganavsargil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adnan Simsir
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ayse Yazici
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Burcin Pehlivanoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cag Cal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sait Sen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Banu Sarsik.

Ethics declarations

Conflicts of Interest

None declared.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sarsik, B., Doganavsargil, B., Simsir, A. et al. P21 and p27 Immunoexpression in Upper Urinary Tract Urothelial Carcinomas. Pathol. Oncol. Res. 22, 839–845 (2016). https://doi.org/10.1007/s12253-016-0075-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-016-0075-4

Keywords

Search

Navigation